An Equal Opportunity Provider and Employer

VETERINARY SERVICES MEMORANDUM NO. 800.110

TO: Veterinary Services Leadership Team

Directors, Center for Veterinary Biologics

Biologics Licensees, Permittees, and Applicants

FROM: Jack A. Shere /s/ Jack Shere June 30, 2017

Deputy Administrator

SUBJECT: Label Warnings Concerning Bovine Rhinotracheitis Vaccine, Modified 

Live Virus, and Bovine Virus Diarrhea Vaccine, Modified Live Virus, for

Pregnant Cows or Calves Nursing Pregnant Cows

I. PURPOSE

This memorandum provides Center for Veterinary Biologics (CVB) guidance for label 

warnings and for claiming exemptions to the warning requirements against the use of 

bovine rhinotracheitis (IBRV) vaccine, modified live virus, and bovine virus diarrhea 

(BVDV) vaccine, modified live virus, in pregnant cows or in calves nursing pregnant 

cows.

II. CANCELLATION

This memorandum cancels Veterinary Services (VS) Memorandum No. 800.110 dated 

October 18, 2004.

III. BACKGROUND

Title 9, Code of Federal Regulations (9 CFR), section 112.7(e)(1) requires labels for 

IBRV and BVDV vaccines containing modified live virus to bear the following 

warning: “Do not use in pregnant cows or in calves nursing pregnant cows.” The 

Administrator, Animal and Plant Health Inspection Service, may grant an exemption to 

this requirement under 9 CFR 113.4(a), provided that such a vaccine has been shown to 

be safe for such use. This memorandum provides guidance concerning the data needed 

to obtain the exemption. The data may also be used to support the label claim “for use in 

pregnant cows or in calves nursing pregnant cows.”

To obtain the exemption to the warning statement and to support the label claim 

(above), supporting studies should be conducted as in section IV.

Animal and Plant

Health Inspection

Service

Veterinary Services

1400 Independence

Ave, SW

Washington, DC

20250
VETERINARY SERVICES MEMORANDUM NO. 800.110

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 An Equal Opportunity Provider and Employer

IV. GUIDELINES

Only heifers and cows that are confirmed pregnant should be included in the study. All animals 

should be vaccinated with an appropriate single or multifraction test vaccine. Animals must be 

vaccinated in accordance with product labeling, including, if recommended, a pre-breeding 

vaccination. If vaccination prior to breeding is not required, all animals must be seronegative

for virus prior to administration of the test vaccine. Studies that involve only the vaccination of

calves that are nursing pregnant heifers or cows will not be acceptable for claiming the 

exemption. Clinical studies should be conducted in accordance with VS Memorandum No.

800.301.

A. Study Design

1. Animals – At least 1,200 pregnant heifers and cows must be included in the study. 

Animals should be divided into three groups of 400 animals each on the basis of

stage of pregnancy; i.e., the first, second, or third trimester.

a. Three separate studies may be conducted; however, at least 400 animals are

needed for each stage of pregnancy.

b. All animals included in the study must be followed through parturition.

2. Randomization – Randomly divide each group (trimester) into two groups 

(vaccinates and controls), each containing 200 animals.

a. Inoculate animals in the vaccinate group with the modified live virus test 

vaccine.

b. Inoculate animals in the control group with inactivated vaccine or phosphate

buffered saline.

c. The groups should be adequately separated so as to prevent the controls from

being exposed to vaccinates that may be shedding vaccine virus.

B. Vaccine

Vaccine used in the study should be formulated in accordance with the filed Outline of

Production. If vaccination prior to breeding is recommended, the identity of the

vaccine used for the pre-breeding vaccination should be specified in the report and on

the labeling.
VETERINARY SERVICES MEMORANDUM NO. 800.110

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 An Equal Opportunity Provider and Employer

C. Data

For each group, the calving rate, the health status of the calves up to 4 weeks postpartum, and the Clopper-Pearson 95% confidence interval for the aborting fraction

should be determined and summarized in the study report.

1. Abortions – Animals that do not deliver a live calf will be counted as abortions,

cause unknown. Abortions due to diagnosed causes other than BVDV or IBRV, as 

applicable, will be excluded from the data analysis.

a. Aborted calves should be necropsied and the results included in the study

report.

b. The study must be repeated for any trimester group in which the rate of

abortion due to any cause exceeds 5%.

c. An exemption may not be approved if the rate of abortion due to IBRV or

BVDV exceeds 0.5% in any trimester group.

2. Fetal Infection, BVDV – To detect BVDV capable of causing fetal infection

without causing abortion, pre-suckling serum samples from at least 100 randomly

chosen calves born from the second and third trimester pregnancy groups

(50/group) should be tested for antibody to types 1 and 2 BVDV and to IBRV; an

exemption may not be approved if any animal has a positive test.

3. Adverse Events Monitoring – The CVB may monitor adverse events reported to the

company and compare the number of adverse event reports per number of doses of

vaccine marketed that have been received by the firm after the exemption to the

number of adverse event reports per number of doses of vaccine marketed that 

have been received by the firm prior to the approval of the exemption. If evidence of

safety problems is encountered, the CVB will take appropriate action(s).

D. Labeling

With the exemption, labeling (including the circular) should include a statement that the

vaccine may be used in pregnant cows and calves nursing pregnant cows, with a brief

description of the study and a summary of the results.

1. Pre-breeding Vaccination – If vaccination prior to breeding is required, the

recommended product and dose should be specified on the label. Multifraction

vaccine(s) produced by the same manufacturer may be recommended provided that

they are produced using the same master seed virus, master cell stock, and serial

release titer as the test vaccine. Wording acceptable to the CVB is “This vaccine

may be used in pregnant cows or calves nursing pregnant cows provided they were

vaccinated, pre-breeding, with <insert product name>.”
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 An Equal Opportunity Provider and Employer

2. Warnings – Labeling must also bear the following statement concerning residual 

risk; see also 9 CFR 112.7(e)(3): “Fetal health risks associated with the 

vaccination of pregnant animals with this vaccine cannot be unequivocally 

determined during clinical trials conducted for licensure. Appropriate strategies to 

address the risks associated with vaccine use in pregnant animals should be 

discussed with a veterinarian.”

3. Aborting Fractions – Because treatment groups may not have been commingled 

during the study, inferences concerning any relationship between the calculated 

aborted fraction(s) for the groups must be reviewed by the CVB.

V. ACTION

Section IV presents the simplest design for a minimally acceptable study. If a firm wishes to 

design a more complex study; e.g., a study that will support between group inference (i.e., that 

includes replication to prevent confounding of treatment and housing), they may do so. 

Protocols should be submitted to the CVB for review prior to the initiation of any study. 

Upon successful completion of a study and acceptance of the data, the CVB will approve an 

exemption to the warning requirement under 9 CFR 112.7(e)(1).

VI. IMPLEMENTATION/APPLICABILITY

This memorandum is effective immediately.